REGULATION OF ANP RECEPTOR ACTIVITY IN VASCULAR CELLS

血管细胞中 ANP 受体活性的调节

• 批准号: 2607119
• 负责人: David G Gardner
• 金额: $ 23.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2607119
• 关键词: atrial natriuretic peptide; body fluid osmolarity; cardiovascular function; cyclic GMP; enzyme activity; gene expression; genetic regulatory element; guanylate cyclase; hormone receptor; hormone regulation /control mechanism; in situ hybridization; laboratory rat; posttranslational modifications; protein structure function; radiotracer; receptor binding; receptor expression; renal tubular transport; spontaneous hypertensive rat; tissue /cell culture; transcription factor; transfection; vascular smooth muscle

DESCRIPTION: (Adapted from the application) The natriuretic peptides represent a family of hormonal, autocrine and paracrine regulators that control cardiovascular homeostasis and fluid balance. They exhibit potent vasodilatory, natriuretic, hypotensive and anti-mitogenic activity in a number of different tissues. They exert these effects through association with high affinity receptors on the surface of target cells and subsequent activation of particulate guanylyl cyclase activity. The latter is encoded at the carboxy terminus of the receptor molecule. The guanylyl cyclase-linked receptors can be separated into two principal forms. The first, NPR-A, binds ANP and BNP with high affinity while NPR-B preferentially associates with CNP. Relatively, little is known about the regulation of these receptors and even less about the expression of their genes. Based on preliminary studies carried out in the investigator's laboratory, as well as other laboratories, it appears that growth status of the target cells, as well as a number of different regulatory factors, control the expression of these genes and the functional activity of their protein products. The focus of the present application will be to dissect the mechanism(s) underlying these regulatory events at the molecular level and to use this information to better understand the physiological or pathophysiological implications of this regulatory activity in the intact animal. Specific aims will include: (1) to identify the cis-elements and associated trans-acting nuclear proteins which govern basal expression of the NPR genes in target cells. Particular attention will be devoted to the identification of regulatory elements which might account for the differential expression and regulation of the NPR-A vs. NPR-B genes, (2) to elucidate the molecular mechanism(s) underlying the cGMP-dependent regulation of NPR-A promoter activity, (3) to determine the etiology of the increase in NPR-A gene expression in ASMC of the SHR (vs. WKY) rat, (4) to identify the mechanism whereby estrogen activates NPR-A promoter activity, (5) to dissect the mechanism linking extracellular hyperosmolality to elevations in NPR-A gene expression. These studies should provide a clearer picture as to how these receptors are regulated physiologically and how malregulation may contribute to the pathophysiology of cardiovascular and renal disease.

描述：（改编自申请）利尿钠肽 代表激素、自分泌和旁分泌调节剂家族 控制心血管稳态和体液平衡。 他们表现出强大的 血管舒张、利尿钠、降血压和抗有丝分裂活性 不同组织的数量。 他们通过关联发挥这些作用 与靶细胞表面的高亲和力受体结合，随后 颗粒鸟苷酸环化酶活性的激活。 后者被编码 位于受体分子的羧基末端。 鸟苷基 环化酶连接的受体可以分为两种主要形式。 这 首先，NPR-A 以高亲和力结合 ANP 和 BNP，而 NPR-B 优先与 CNP 合作。 相对而言，人们对此知之甚少 这些受体的调节，甚至更不用说它们的表达 基因。 根据研究者进行的初步研究 实验室以及其他实验室，似乎生长状况 靶细胞以及许多不同的调节因子， 控制这些基因的表达及其功能活性 蛋白质产品。 本申请的重点是剖析 这些调控事件在分子水平上的潜在机制 并利用这些信息更好地了解生理或 这种调节活动在完整细胞中的病理生理学意义 动物。 具体目标包括：（1）确定顺式元素和 相关的反式作用核蛋白，控制基础表达 靶细胞中的 NPR 基因。 将特别关注 识别可能解释的监管要素 NPR-A 与 NPR-B 基因的差异表达和调节，(2) 至 阐明 cGMP 依赖性的分子机制 NPR-A启动子活性的调节，（3）确定病因 SHR（与 WKY）大鼠 ASMC 中 NPR-A 基因表达增加，(4) 确定雌激素激活 NPR-A 启动子活性的机制， (5) 剖析细胞外高渗透压与 NPR-A 基因表达升高。 这些研究应该提供更清晰的 了解这些受体如何进行生理调节以及如何进行调节 调节失调可能会导致心血管和疾病的病理生理学 肾脏疾病。